Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene

Behavioral and biochemical studies suggest that dopamine (DA) plays a role in the reinforcing and addictive properties of drugs of abuse. Recently, th is hypothesis has been challenged on the basis of the observation that, in mice genetically lacking the plasma membrane dopamine transporter [DAT-knoc k out (DAT-KO)], cocaine maintained its reinforcing properties of being sel f-administered and inducing place preference, despite the failure to increa se extracellular dopamine in the dorsal striatum. Here we report that, in D AT-KO mice, cocaine and amphetamine increase dialysate dopamine in the medi al part of the nucleus accumbens. Moreover, reboxetine, a specific blocker of the noradrenaline transporter, increased DA in the nucleus accumbens of DAT-KO but not of wild-type mice; in contrast, GBR 12909, a specific blocke r of the dopamine transporter, increased dialysate dopamine in the nucleus accumbens of wild-type but not of DAT-KO mice. These observations provide a n explanation for the persistence of cocaine reinforcement in DAT-KO mice a nd support the hypothesis of a primary role of nucleus accumbens dopamine i n drug reinforcement.